Dual Anticoagulant and Antiplatelet Therapy for Coronary Artery Disease and Peripheral Artery Disease Patients.

Atherosclerosis is an arterial disease that progresses with age and affects many people in the world. In the United States and Western Europe, cardiovascular disease (CVD) caused by atherosclerosis is the leading cause of death. In advanced atherosclerosis, there is narrowing of the arterial lumen to the extent that tissue ischemia can occur when metabolic demands increase (eg, coronary ischemia with angina). In severe cases, acute rupture or erosion of atherosclerotic plaques lead to the rapid formation of intravascular thrombi, a process referred to atherothrombosis. Clinical manifestations of atherothrombosis occur in the heart (coronary artery disease [CAD] and myocardial infarction [MI]), brain (ischemic stroke), and peripheral arteries (peripheral artery disease [PAD]). CAD can be divided into stable disease and unstable disease that includes acute coronary syndrome (ACS) with ST-segment–elevation MI (STEMI) or non-STEMI. Arterial thrombi are primarily composed of platelets (so-called white clots). However, cross-linked fibrin strands stabilize the clot. Plaques contain many platelet activators, including collagen (Figure). In addition, plaques contain high levels of tissue factor that activates the coagulation cascade (Figure). Importantly, platelets and the coagulation cascade are activated in parallel, and there is crosstalk between the 2 pathways. For instance, thrombin is a potent activator of human platelets through cleavage of protease-activated receptors (PARs; PAR1 and PAR4), and fibrinogen is used to bridge activated platelets. Conversely, activated platelets enhance coagulation by providing coagulation factors and by presenting a negatively charged phospholipid surface that facilitates the assembly of cofactor/coagulation protease complexes and thrombin generation. Platelet inhibitors are the primary therapy used to prevent arterial thrombosis in CVD patients. The standard medical treatment for ACS patients and patients receiving percutaneous coronary intervention (PCI) with an intracoronary stent is dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 inhibitor. Aspirin irreversibly inhibits cyclooxygenase-1 and prevents platelet-dependent thromboxane formation. P2Y12 inhibitors include thienopyridines, such as clopidogrel and prasugrel, and cyclopentyltriazolopyrimidine-type inhibitors, such as ticagrelor. Clopidogrel and prasugrel are prodrugs that require activation by cytochrome P450 enzymes in the liver. Ticagrelor is a direct acting noncompetitive inhibitor of P2Y12. DAPT is recommended for a minimum of 6 months in patients with stable CAD receiving a drug-eluting stent and for 12 months in patients with ACS (the majority of whom undergo PCI with stenting). After this time, therapy can be changed to a single antiplatelet agent depending on the balance between risk of recurrent ischemic event versus risk of bleeding with DAPT. Despite continued antiplatelet therapy, patients remain at risk for recurrent cardiovascular events, particularly in those at highest risk, such as patients with diabetes mellitus, PAD, and complex CAD. The current recommended treatment for patients with stable CAD is low-dose aspirin or clopidogrel if they do not tolerate aspirin. The recommended treatment for patients with PAD is single antiplatelet therapy. However, despite antiplatelet therapy, ≈2% to 5% of CAD and PAD patients annually have major adverse cardiovascular events. Clinical trials have compared the efficacy and safety of different antiplatelet agents and combinations of antiplatelet agents in CVD patients, attempting to find more effective and safer strategies to prevent recurrent atherothrombotic events (Table). A recent review discusses these different trials in detail. In this brief review, we selected a few trials to illustrate differences between trials and the relationship between efficacy and safety. Comparison of different trials is difficult because they are performed at different times and include different groups of patients. The TRITON-TIMI 38 trial (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with PrasugrelThrombolysis in Myocardial Infarction 38) enrolled >13 000 patients with ACS (either STEMI or nonSTEMI) of which 99% underwent PCI. The more potent P2Y12 blocker prasugrel was superior to clopidogrel in reducing the combined end point of vascular death, MI, or stroke in patients with ACS, but there was a higher rate of bleeding with